What's the science?
In some psychiatric disorders (e.g. schizophrenia), communication between neurons in the brain (via synapses: the connections between neurons) is altered. Lysophosphatidic acid (LPA) signaling in the brain’s synapses is also known to be altered in psychiatric disorders, leading to hyperexcitability in the brain (a loss of balance between excitation and inhibition due to increased excitation of glutamatergic (i.e. excitatory) neurons). LPA is synthesized by the enzyme autotaxin, but we don’t know what the source of LPA is in the synapse. This week in Molecular Psychiatry, Thalman and colleagues explored the source of LPA in the brain, and whether inhibition of autotaxin could control hyperexcitability in the brain.
How did they do it?
Experiments were performed using mice. First, the authors used immunohistochemistry and electron microscopy techniques to assess whether autotaxin was colocalized with excitatory or inhibitory neurons, and where in the synapse autotaxin was located. Next, they imaged astrocytes in vivo using green fluorescent protein, to assess whether autotaxin transport was occurring within astrocyte endfeet (i.e. processes) near synapses. The authors also examined knockout mice without a gene that regulates/lowers LPA levels (PRG-1-/- mice), and mice without autotaxin in astrocytes (ATXfl/fl). Finally, in a ketamine animal model of schizophrenia (ketamine induces hyperexcitability), the authors explored the potential of an autotaxin inhibitor on hyperexcitability.
What did they find?
The authors found that autotaxin was colocalized with excitatory neurons but not inhibitory neurons. Specifically, autotaxin was present in astrocyte processes at these synapses. They confirmed the location of autotaxin in astrocyte processes of both the hippocampus and cortex using electron microscopy. Using green fluorescent protein to image autotaxin, they found that it’s transport within the astrocytes was stimulated via glutamate (excitatory neurotransmitter). In mice with PRG-1 deletion (causing dysregulated LPA), autotaxin inhibition reduced excitation (excitatory post-synaptic currents) of pyramidal neurons in the hippocampus to normal levels, but in normal mice, autotaxin inhibition did not reduce excitation. This indicates that autotaxin inhibition can bring activity levels back to normal in hyperexcitable neurons. A similar observation was made when autotaxin was genetically deleted in astrocytes (ATXfl/fl mice). In a ketamine animal model of schizophrenia, ketamine caused cortical hyperexcitability as expected, while autotaxin inhibition reduced it to normal levels. Autotaxin inhibition also reduced behaviors associated with hyperexcitability such as hyperlocomotion to normal levels.
What's the impact?
In this study, the authors explored regulation of a phospholipid (LPA) known to regulate cortical excitability and be disrupted in psychiatric disorders. This study demonstrates that autotaxin from astrocytes at the synapse are likely responsible for regulating LPA levels and therefore cortical hyperexcitability. Targeting autotaxin could prove viable in reducing cortical hyperexcitability and related behavioral symptoms associated with psychiatric disorders.
Thalman et al., Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders. Molecular Psychiatry (2018). Access the original scientific publication here.